Variant rs144800506 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_194248.3(OTOF):c.2375G>T(p.Arg792Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R792Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

Variant links:

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2375G>T	p.Arg792Leu	missense_variant	20/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.134G>T	p.Arg45Leu	missense_variant	3/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2375G>T	p.Arg792Leu	missense_variant	20/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.134G>T	p.Arg45Leu	missense_variant	3/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000442

AC:

AN:

226462

Hom.:

AF XY:

0.00000817

AC XY:

AN XY:

122440

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000583

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447812

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

.;.;.;D;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D

MetaSVM

Uncertain

-0.046

MutationAssessor

Uncertain

2.6

.;.;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.0

D;D;.;D;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

D;D;.;D;D;.

Sift4G

Uncertain

0.0070

D;D;.;D;D;.

Polyphen

0.41

B;B;.;B;.;P

Vest4

0.81

MutPred

0.35

.;.;.;Loss of MoRF binding (P = 0.0351);Loss of MoRF binding (P = 0.0351);.;

MVP

0.90

MPC

0.22

ClinPred

0.98

GERP RS

3.8

Varity_R

0.62

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over